Ocular Surface最新文献

英文中文

Letter to the Editor regarding “Corneal sensory nerve regulation of tear production through stimulation of transient receptor potential melastatin 8 (TRPM8) channel: A potential new approach for treating dry eye disease” 致编辑关于“角膜感觉神经通过刺激瞬时受体电位美拉他汀8 （TRPM8）通道调节泪液产生：一种治疗干眼病的潜在新方法”的信

IF 5.6 1区医学 Q1 OPHTHALMOLOGY

Ocular Surface

Pub Date : 2025-09-20 DOI: 10.1016/j.jtos.2025.09.002

Parth Aphale, Shashank Dokania, Himanshu Shekhar

引用次数: 0

Downregulation of the core circadian gene Nr1d2 in the lacrimal gland contributes to postoperative dry eye disease by impairing lipid metabolism 泪腺核心昼夜节律基因Nr1d2的下调通过损害脂质代谢参与术后干眼病

IF 5.6 1区医学 Q1 OPHTHALMOLOGY

Ocular Surface

Pub Date : 2025-08-28 DOI: 10.1016/j.jtos.2025.08.009

Shiji Liu , Yuke Huang , Xi Chen , Huanhuan Ren, Jiaxin Chen, Qingqing Mu, Jiejie Zhuang, Yan Li, Jin Qiu, Keming Yu, Jing Zhuang

Purpose

Dry eye disease (DED) is a prevalent complication after refractive surgery, and its underlying mechanisms are not fully understood. Given that circadian rhythm tightly regulates tear secretion, this study aims to investigate the circadian changes in the lacrimal gland after corneal refractive surgery and the associated mechanisms.

Methods

C57/BL6 mice underwent corneal epithelial abrasion and stromal severing. DED was assessed using phenol red thread and fluorescein staining. RNA sequencing identified differentially expressed genes (DEGs) related to circadian rhythm, validated by RT-qPCR and Western blotting. Immunofluorescence, TUNEL staining, untargeted metabolomics, Oil-Red-O staining, and TEM were performed to analyze the lacrimal gland changes. Clinically, DED symptoms were evaluated using the OSDI questionnaire in 867 post-surgical patients and 705 controls.

Results

Corneal epithelial abrasion and stromal severing induced DED symptoms and lacrimal dysfunction, including reduced tear volume, ocular surface inflammation, and lacrimal pathophysiological changes. Nr1d2, the key circadian rhythm gene, was significantly down-regulated in the lacrimal gland compared to the control. Activation of Nr1d2 with SR9011 restored the lacrimal gland function and alleviated DED symptoms. Furthermore, the down-regulation of Nr1d2 significantly impaired lipid metabolism and mitochondrial function in the lacrimal gland, which SR9011 reversed. Clinically, the incidence of DED was markedly higher in the surgical cohort, with symptom occurrence exhibiting diurnal variation and peaking in the early morning and late evening.

Conclusions

Disruption of circadian rhythms, specifically Nr1d2 downregulation, contributes to post-surgical DED. Targeting Nr1d2 may offer a novel therapeutic approach to restore lacrimal gland function and alleviate DED.

目的：干眼病是屈光手术后常见的并发症，其发病机制尚不完全清楚。鉴于昼夜节律紧密调控泪液分泌，本研究旨在探讨角膜屈光手术后泪腺的昼夜节律变化及其机制。方法：对C57/BL6小鼠进行角膜上皮磨损和间质切断。采用酚红线和荧光素染色评价DED。RNA测序鉴定出与昼夜节律相关的差异表达基因（DEGs），并通过RT-qPCR和Western blotting验证。采用免疫荧光、TUNEL染色、非靶向代谢组学、Oil-Red-O染色和透射电镜分析泪腺的变化。临床应用OSDI问卷对867例术后患者和705例对照患者进行DED症状评估。结果：角膜上皮磨损和间质损伤引起DED症状和泪液功能障碍，包括泪液量减少、眼表炎症和泪液病理生理改变。与对照组相比，关键的昼夜节律基因Nr1d2在泪腺中显著下调。SR9011激活Nr1d2恢复泪腺功能，缓解DED症状。此外，Nr1d2的下调显著损害了泪腺的脂质代谢和线粒体功能，SR9011逆转了这一变化。临床上，手术组DED的发生率明显较高，且症状呈现昼夜变化，在清晨和傍晚达到高峰。结论：昼夜节律的破坏，特别是Nr1d2的下调，有助于术后DED。靶向Nr1d2可能为恢复泪腺功能和缓解DED提供新的治疗途径。

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引用次数: 0

L009 peptide as a novel antiangiogenic agent for corneal neovascularization via regulation of the TNFSF15-VEGF axis L009肽通过调节TNFSF15-VEGF轴作为角膜新生血管的新型抗血管生成剂

IF 5.6 1区医学 Q1 OPHTHALMOLOGY

Ocular Surface

Pub Date : 2025-08-27 DOI: 10.1016/j.jtos.2025.08.008

Ke Yan , Yiran Yang , Yi Han , Yuhan Zhang , Tong Zhou , Wenxin Sun , Ruochen Wang , Zhaolin Liu , Qinghe Zhang , Linfangzi Zhu , Meidi Tan , Caihong Huang , Jiaoyue Hu , Qiuping Liu , Zhaoqiang Zhang , Zuguo Liu

Corneal neovascularization (CNV) is a leading cause of vision impairment, with existing therapeutic options offering limited efficacy. This study presents L009, a novel antiangiogenic agent derived from the Kringle 5 domain of human plasminogen, specifically a heptapeptide, designed to treat CNV. In preclinical models, L009 demonstrated substantial efficacy by markedly inhibiting endothelial cell proliferation and migration, reducing vascular permeability, and maintaining ocular safety. Mechanistically, L009 exerts its effects by upregulating tumor necrosis factor superfamily member 15 (TNFSF15), downregulating vascular endothelial growth factor receptor 2 (VEGFR2), and increasing the expression of soluble VEGFR1. These actions restore vascular homeostasis and enhance vascular stability through the upregulation of the tight junction protein VE-cadherin. By specifically targeting the TNFSF15-VEGF axis, L009 offers a distinctive therapeutic approach, differentiating it from conventional anti-VEGF therapies. Its dual action of anti-angiogenesis and promotion of vascular stability highlights its potential as a next-generation treatment for CNV. Further investigation into its long-term efficacy and potential for synergy with existing therapies is warranted.

角膜新生血管（CNV）是视力损害的主要原因，现有的治疗方案提供有限的疗效。本研究提出了一种新型抗血管生成药物L009，该药物来源于人纤溶酶原的Kringle 5结构域，特别是一种七肽，旨在治疗CNV。在临床前模型中，L009通过显著抑制内皮细胞增殖和迁移，降低血管通透性，维持眼部安全，显示出实质性的疗效。在机制上，L009通过上调肿瘤坏死因子超家族成员15 (TNFSF15)，下调血管内皮生长因子受体2 (VEGFR2)，增加可溶性VEGFR1的表达来发挥作用。这些作用通过上调紧密连接蛋白ve -钙粘蛋白恢复血管稳态，增强血管稳定性。通过特异性靶向TNFSF15-VEGF轴，L009提供了一种独特的治疗方法，将其与传统的抗vegf疗法区分开来。其抗血管生成和促进血管稳定性的双重作用突出了其作为新一代CNV治疗的潜力。进一步研究其长期疗效和与现有疗法协同作用的潜力是必要的。

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引用次数: 0

Two models of the structures of the lamellae in human meibum and the tear film lipid layer, TFLL 人体膜层和泪膜脂层的两种结构模型。

IF 5.6 1区医学 Q1 OPHTHALMOLOGY

Ocular Surface

Pub Date : 2025-08-21 DOI: 10.1016/j.jtos.2025.08.006

P. Ewen King-Smith , Carolyn G. Begley , Richard J. Braun

Two models of meibum and the TFLL are proposed. The first model is based on a reanalysis of x-ray studies which show the predominance of 11 nm thick lamellae above 30 °C, but below 30 °C, 5 nm thick lamellae predominate. By analogy to skin lipid, we denote these the long (LPP) and short period phase (SPP), respectively. In the model, the SPP lamellae are interdigitated bilayers of cholesteryl esters (CEs) oriented towards one surface and wax esters (WEs) oriented towards the other surface, with the long interdigitated CE and WE chains tilted. These lamellae are stacked with the same polarity, e.g., CE surface uppermost. At ocular surface temperature, the polarity of alternate layers is reversed, forming the LPP. This doubles the periodicity, but the tilt of the LPP long chains is reduced to render the periodicity more than twice the SPP. The model is consistent with changes in meibum near 30 °C found in calorimetry, viscoelasticity, infrared spectra, birefringence, reflectance, and high resolution images of meibum spread on saline. A secondary model explains the finding that most long saturated chains in CEs and WEs are branched. We propose a ‘bump and hollow’ model where a ‘bump’ is a branch on a WE chain fitting into a ‘hollow’, the linking oxygen atom in a neighboring CE chain; likewise, a bump on a CE chain fits a hollow on a WE chain. We aim to stimulate further development of lipid layer models, including the role of other molecules, to aid understanding of dry eye disease (DED).

提出了两种模型，分别是meibum模型和tfl模型。第一个模型是基于x射线研究的再分析，该研究表明，在30℃以上，11 nm厚的片层占主导地位，但在30℃以下，5 nm厚的片层占主导地位。与皮肤脂质类似，我们将它们分别称为长周期（LPP）和短周期（SPP）。在该模型中，SPP片层是面向一个表面的胆甾醇酯（CEs）和面向另一个表面的蜡酯（WEs）的交错双分子层，长交错的CE和WE链倾斜。这些片层以相同的极性堆叠，例如CE表面最上层。在眼表温度下，交替层的极性颠倒，形成LPP。该模型与热量法、粘弹性、红外光谱、双折射、反射率和高分辨率盐水中mebum分布的图像中发现的30℃附近mebum的变化一致。第二个模型解释了ce和WEs中大多数长饱和链是分支的这一发现。我们提出了一个“凹凸和空心”模型，其中“凹凸”是We链上的一个分支，与相邻CE链上的连接氧原子“空心”相吻合；同样，CE链上的凸起与WE链上的空洞相吻合。我们的目标是刺激脂质层模型的进一步发展，包括其他分子的作用，以帮助理解干眼病（DED）。

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引用次数: 0

IVCM image analysis for limbal stem cell deficiency: quantitative diagnostics of the corneal epithelium post-transplant recovery 角膜缘干细胞缺乏的IVCM图像分析：角膜上皮移植后恢复的定量诊断

IF 5.6 1区医学 Q1 OPHTHALMOLOGY

Ocular Surface

Pub Date : 2025-08-20 DOI: 10.1016/j.jtos.2025.08.005

Patrick Parkinson , Irina Makarenko , Oliver J. Baylis , Gustavo S. Figueiredo , Majlinda Lako , Anvar Shukurov , Francisco C. Figueiredo , Laura E. Wadkin

Purpose

Limbal stem cell deficiency (LSCD), a sight-threatening condition, is caused by dysfunction of the limbal stem cells (LSCs) which maintain the corneal epithelium. An effective treatment of LSCD is the transplantation of ex-vivo cultured LSCs from the patient's healthy other eye (in unilateral cases) or a donor eye (in bilateral cases) to the affected eye. Here we identify and quantify diagnostic and monitoring criteria for the recovery of the corneal epithelium post-LSC transplant using cellular images.

Methods

We consider the in-vivo confocal microscopy (IVCM) images from 10 patients with total unilateral LSCD caused by chemical burns, taken before and after LSC transplant. Images encompass the entire thickness of the corneal epithelium in the central and four peripheral regions. Approximately 1500 images were segmented using a bespoke algorithm to extract morphological data for analysis.

Results

The probability density of cell areas is shown to be a sensitive monitoring tool of corneal epithelial status. After a successful operation the distribution of cell areas is rather flat, reflecting an anomalously wide range of cell areas. As the cornea recovers, the distribution narrows with high statistical confidence and approaches that of the healthy cornea. We find a strong patient-to-patient variability in the epithelial cell area distribution and its variation with corneal depth. The corneal epithelial cell shape is independent of the cornea status despite a widespread expectation that healthy cells are roughly hexagonal.

Conclusion

Cell area is a sensitive and easily accessible marker of corneal epithelial recovery in LSCD patients post-LSC transplant.

角膜缘干细胞缺乏症（LSCD）是由维持角膜上皮的角膜缘干细胞（LSCs）功能障碍引起的一种视力威胁疾病。LSCD的一种有效治疗方法是将离体培养的LSCs从患者健康的另一只眼（单侧病例）或供体眼（双侧病例）移植到受影响的眼睛。在这里，我们使用细胞图像确定和量化lsc移植后角膜上皮恢复的诊断和监测标准。

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引用次数: 0

Economic burden of keratitis patients with inpatient care: a nationwide, multicenter registry study 住院治疗角膜炎患者的经济负担：一项全国性、多中心登记研究

IF 5.6 1区医学 Q1 OPHTHALMOLOGY

Ocular Surface

Pub Date : 2025-08-19 DOI: 10.1016/j.jtos.2025.08.007

He Xie , Hai Liu , Chenxi Wang , Kexin Tang , Qinxiang Zheng , Kaisheng Wang , Baihua Chen , He Dong , Feng Wen , Tao Sun , Jizhong Yang , Yanning Yang , Limin Chen , Zhirong Liu , Shaozhen Zhao , Wei Qiang , Qi Xie , Yuping Han , Linying Huang , Man Yu , Wei Chen

引用次数: 0

Pipeline: Patient, physician and developer view of drugs vs. devices 管道：患者、医生和开发人员对药物与设备的看法

IF 5.6 1区医学 Q1 OPHTHALMOLOGY

Ocular Surface

Pub Date : 2025-08-18 DOI: 10.1016/j.jtos.2025.08.004

Gary D. Novack

引用次数: 0

Clinical recommendations for the management of Pythium insidiosum keratitis 治疗藏皮角膜炎的临床建议

IF 5.6 1区医学 Q1 OPHTHALMOLOGY

Ocular Surface

Pub Date : 2025-08-18 DOI: 10.1016/j.jtos.2025.08.003

Bhupesh Bagga , Lakshminarayanan Gowtham , Ali R. Djalilian , Savitri Sharma

Pythium insidiosum has emerged as a challenging cause of keratitis in recent decades, due to its unique microbiological and clinical features, often is mistaken for fungal keratitis. Anti-fungal therapies have proven ineffective due to the organism's distinct cellular structure. Based on in vitro and in vivo models there has been a shift towards the use of antibacterial agents like linezolid and azithromycin, which have shown promising results. This concise review provides an update on the recommended diagnostic techniques and management strategies to assist clinicians in navigating this complex disease landscape.

近几十年来，由于其独特的微生物学和临床特征，二氧化钛已成为角膜炎的一个具有挑战性的原因，经常被误认为是真菌性角膜炎。抗真菌疗法已被证明无效，由于生物体的独特的细胞结构。在体外和体内模型的基础上，已经转向使用抗菌药物，如利奈唑胺和阿奇霉素，这些药物已经显示出有希望的结果。这篇简明的综述提供了最新的推荐诊断技术和管理策略，以帮助临床医生在这种复杂的疾病景观中导航。

引用次数: 0

Exploration of imaging and molecular biomarkers for differentiation of neuropathic corneal pain from dry eye syndrome 神经病变性角膜疼痛与干眼综合征鉴别的影像学及分子标志物探讨。

IF 5.6 1区医学 Q1 OPHTHALMOLOGY

Ocular Surface

Pub Date : 2025-08-14 DOI: 10.1016/j.jtos.2025.08.002

Jun Cheng , Chang Liu , Mingyi Yu , Isabelle Xin Yu Lee , Xinyue Wang , Victor Wei-Tse Hsu , Aya Takahashi , Jodhbir S. Mehta , Lei Zhou , Louis Tong , Yu-Chi Liu

Purpose

To investigate the imaging, clinical, and tear proteomic profiles between neuropathic corneal pain (NCP) and dry eye disease (DED), and to identify potential imaging and molecular biomarkers for the differentiation of NCP from DED.

Methods

This cross-sectional study included 54 NCP patients (105 eyes), 53 DED patients (106 eyes), and 54 healthy controls (108 eyes). All subjects were evaluated with ocular surface assessment, ocular pain assessment survey (OPAS), and in-vivo confocal microscopy to characterize corneal nerves, microneuromas (MNs), immune cells, and epithelial cells. Tear quantitative proteomics were analyzed.

Results

The percentage of presence of MNs, the number, total area, total perimeter, and average area of MNs were significantly higher in the NCP group than the other two groups. NCP patients had significantly higher corneal nerve fiber width. MNs parameters were significantly correlated with the OPAS scores (r = 0.20 to 0.48, all P < 0.05). Particularly, in peripheral NCP, both MNs total area and perimeter exhibited a significant correlation with the OPAS eye pain intensity (r = 0.55–0.57, both P < 0.05). Combinations of MNs parameters and OPAS scores had high diagnostic efficacy for NCP with an area under the curve (AUC) of 0.916. A total of 129 significantly differential proteins were identified, such as up-regulated vinculin and down-regulated DLG associated protein 4 in NCP, as well as up-regulated S100A12 and matrix metallopeptidase 9 in DED. These dysregulated proteins were linked to neuron apoptosis, inflammatory response, and synaptic transmission.

Conclusion

NCP patients present with different imaging features, clinical characteristics and proteomic profiles, compared with DED patients. These can be used as differentiating indicators.

目的：探讨神经性角膜疼痛（NCP）和干眼病（DED）的影像学、临床和泪液蛋白质组学特征，并寻找区分NCP和DED的潜在影像学和分子生物标志物。方法：本横断面研究纳入54例NCP患者（105眼）、53例DED患者（106眼）和54例健康对照（108眼）。通过眼表评估、眼痛评估调查（OPAS）和体内共聚焦显微镜对所有受试者进行评估，以表征角膜神经、微神经瘤（MNs）、免疫细胞和上皮细胞。泪液定量蛋白质组学分析。结果：NCP组MNs的出现率、数目、总面积、周长及平均面积均显著高于其他两组。NCP患者角膜神经纤维宽度明显增高。MNs参数与OPAS评分显著相关（r=0.20 ~ 0.48）。结论：与DED患者相比，NCP患者表现出不同的影像学特征、临床特征和蛋白质组学特征。这些可以用作区分指标。

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引用次数: 0

Differences in pre-surgical baseline tear proteome are associated with persistent post-refractive surgery pain 术前撕裂蛋白组基线差异与屈光术后持续疼痛有关。

IF 5.6 1区医学 Q1 OPHTHALMOLOGY

Ocular Surface

Pub Date : 2025-08-10 DOI: 10.1016/j.jtos.2025.08.001

Brooke M. Harkness , Siting Chen , Ashok P. Reddy , Kilsun Kim , Deborah M. Hegarty , Steven J. Everist , Julie A. Saugstad , Jodi Lapidus , Anat Galor , Sue A. Aicher

Purpose

Most patients who undergo refractive surgery have excellent outcomes, but a subset experience persistent eye pain after the procedure. We hypothesized that pre-operative tear fluid proteins are distinct in patients who develop pain after surgery.

Methods

Patients undergoing refractive surgery (LASIK or PRK) provided tear fluid samples and eye pain reports (numeric rating scale (NRS) 0–10) before (baseline) and after surgery. Patients reporting no baseline pain, but pain (NRS ≥3) at 3 months (Pain group, n = 31), were compared to patients with no pain before or 3 months after surgery (No Pain group, n = 47). Baseline samples were analyzed by tandem mass tag spectrometry. Proteins demonstrating differential expression based on fold change thresholds, area under the ROC curve (AUC), or feature importance in random forest classification were identified and used to construct multi-protein models.

Results

Thirty-nine proteins showed differential expression between Pain and No Pain patients. Multi-protein models showed that a subset of 4 proteins classified the Pain group with an AUC of 0.87 (95 % CI, 0.79–0.96). This model contained 2 proteins that increased (PGRC1 and PFD3) and 2 proteins that decreased (IBP3 and SPB9) in Pain patients, showing bi-directional, dynamic effects.

Conclusion

Analysis of pre-surgical tears reveals proteome differences in patients who go on to experience persistent pain 3 months after refractive surgery. Since these tear samples were taken prior to surgery, when patients were not experiencing pain, these protein patterns may inform the discovery of risk biomarkers for persistent post-refractive surgery eye pain.

目的：大多数接受屈光手术的患者都有很好的结果，但有一部分患者在手术后会经历持续的眼睛疼痛。我们假设术前泪液蛋白在术后出现疼痛的患者中是不同的。方法：接受屈光手术（LASIK或PRK）的患者在术前（基线）和术后提供泪液样本和眼部疼痛报告（数值评定量表（NRS） 0 - 10）。无基线疼痛，但3个月时疼痛（NRS bbbb3）的患者（疼痛组，n=31）与术前或术后3个月无疼痛的患者（无疼痛组，n=47）进行比较。基线样品采用串联质谱分析。基于折叠变化阈值、ROC曲线下面积（AUC）或随机森林分类中特征重要性的差异表达蛋白被识别并用于构建多蛋白模型。结果：39个蛋白在疼痛组和无疼痛组有差异表达。多蛋白模型显示，4种蛋白组成的子集将疼痛组分类，AUC为0.87 （95% CI, 0.79 - 0.96）。该模型在Pain患者中含有2种升高的蛋白（PGRC1和PFD3）和2种降低的蛋白（IBP3和SPB9），呈双向动态作用。结论：对术前撕裂的分析揭示了屈光手术后3个月持续疼痛患者的蛋白质组差异。由于这些泪液样本是在手术前采集的，当患者没有疼痛时，这些蛋白质模式可能有助于发现屈光手术后持续眼睛疼痛的风险生物标志物。

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